| First Author | Rosin NL | Year | 2015 |
| Journal | Am J Pathol | Volume | 185 |
| Issue | 3 | Pages | 631-42 |
| PubMed ID | 25701883 | Mgi Jnum | J:220249 |
| Mgi Id | MGI:5634033 | Doi | 10.1016/j.ajpath.2014.11.009 |
| Citation | Rosin NL, et al. (2015) Disruption of collagen homeostasis can reverse established age-related myocardial fibrosis. Am J Pathol 185(3):631-42 |
| abstractText | Heart failure, the leading cause of hospitalization of elderly patients, is correlated with myocardial fibrosis (ie, deposition of excess extracellular matrix proteins such as collagen). A key regulator of collagen homeostasis is lysyl oxidase (LOX), an enzyme responsible for cross-linking collagen fibers. Our objective was to ameliorate age-related myocardial fibrosis by disrupting collagen cross-linking through inhibition of LOX. The nonreversible LOX inhibitor beta-aminopropionitrile (BAPN) was administered by osmotic minipump to 38-week-old C57BL/6J male mice for 2 weeks. Sirius Red staining of myocardial cross sections revealed a reduction in fibrosis, compared with age-matched controls (5.84 +/- 0.30% versus 10.17 +/- 1.34%) (P < 0.05), to a level similar to that of young mice at 8 weeks (4.9 +/- 1.2%). BAPN significantly reduced COL1A1 mRNA, compared with age-matched mice (3.5 +/- 0.3-fold versus 15.2 +/- 4.9-fold) (P < 0.05), suggesting that LOX is involved in regulation of collagen synthesis. In accord, fibrotic factor mRNA expression was reduced after BAPN. There was also a novel increase in Ly6C expression by resident macrophages. By interrupting collagen cross-linking by LOX, the BAPN treatment reduced myocardial fibrosis. A novel observation is that BAPN treatment modulated the transforming growth factor-beta pathway, collagen synthesis, and the resident macrophage population. This is especially valuable in terms of potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis. |
